Immunotherapy Developments in Non–Small-Cell Lung Cancer Therapy

When first seen by a physician, 25% to 30% of patients with non–small-cell lung cancer (NSCLC) already have locally advanced disease. Standard treatment for these patients has been platinum-based chemotherapy plus radiation (chemoradiation), which achieved a median

progression-free survival (PFS) of approximately 8 months and a 5-year overall survival (OS) rate of 15% to 30%. Recent developments in immunotherapy have provided significant advances in the treatment of NSCLC.

At the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium, Scott J. Antonia, MD, PhD, Director, Center for Cancer Immunotherapy, Duke Cancer Institute, Durham, NC, reported results of the global phase 3 PACIFIC trial. Improved survival was demonstrated in this trial with durvalumab, an immune checkpoint inhibitor that was used after patients had received chemoradiation. Study results support the use of durvalumab as standard immunotherapy for patients with inoperable stage III NSCLC whose disease has not progressed following chemoradiation.

Within the body’s immune system, immune checkpoint proteins help regulate the immune response so that foreign cells, such as cancer cells, are recognized and attacked while normal cells are left alone. However, certain cancer cells can use these checkpoint proteins to avoid being attacked. If PD-L1 (programmed death ligand 1), a protein found on the surface of some cancer cells, joins with PD-1 (programmed death 1), a protein found on T cells in the immune system, the T cells are no longer able to attack the cancer cells. As an anti–PD-1 checkpoint inhibitor, durvalumab blocks PD-L1 from binding to PD-1, thus allowing T cells to destroy the cancer cells.

During the PACIFIC trial, patients with inoperable NSCLC received either durvalumab (n = 473) or placebo (n = 236) after chemoradiation. At a median follow-up of 25.2 months, the

OS rate significantly improved among the patients who received durvalumab compared with those who received placebo. Durvalumab also improved OS in all prespecified subgroups. The PFS rate was also improved in the durvalu­mab group compared with the placebo group (17.2 vs 5.6 months, respectively).

An interesting observation is that nonsmokers don’t usually respond as well to immunotherapy as smokers do, but the nonsmokers responded equally well to durvalumab in this study. “Nonsmoking patients, both stage IIIa and IIIb, as well as those with squamous and nonsquamous histologies, benefited from durvalumab,” Dr. Antonia observed. “At least in terms of PFS, patients with EGFR mutations also had at least an indication of a benefit but [there were] nowhere near enough patients in this study to draw any firm conclusions about OS.”

Among enrolled patients, 37% had enough tissue to be tested for PD-L1 expression before chemoradiation. A prespecified analysis of PD-L1 expression using a 25% cutoff value was planned, and a PD-L1 expression cutoff value of 1% was part of an unplanned analysis requested by a health authority after the study was completed. PD-L1 status was not available for approximately 25% of the patients.

Dr. Antonia reported that in patients with a PD-L1 value of at least 1%, OS was increased with use of durvalumab, but in those with PD-L1 expression less than 1%, OS was better with placebo.

The median time to distant metastasis was 28.3 months in the durvalumab group versus 16.2 months in the placebo group. The incidence of new tumors was less in the durvalumab group than in the placebo group (22.5% vs 33.8%, respectively).

Durvalumab was well tolerated: 30.5% of the durvalumab patients and 26.1% of the placebo patients had grade 3 or grade 4 adverse events, and adverse events of any grade that caused patients to drop out of the study occurred in 15.4% of durvalumab patients and 9.8% of placebo patients. Pneumonitis (inflammation of the lung tissue) of any grade was more common in the durvalumab group compared with the placebo group (33.9% vs 24.8%, respectively), but there was no difference in number of deaths caused by pneumonitis.

“Five, 6, or 7 years ago as the data were emerging that anti–PD-1 or anti–PD-L1 had very significant clinical impact on advanced NSCLC, we and others began to think about how we could move this into earlier stages [of treatment],” Dr. Antonia explained. At that time, investigators hypothesized that administering anti–PD-1 therapy immediately after chemoradiation would improve survival for patients with NSCLC.

Some of the current research is evaluating anti–PD-1 therapy for patients with stage I/III NSCLC and operable tumors. Consolidation therapy is treatment designed to kill any cancer cells that may remain in the body, and recent data show the value of anti–PD-1 as consolidation therapy after chemoradiation in stage III NSCLC. It is also being studied in patients with inoperable stage I/II disease in combination with stereotactic body radiation therapy, a technique that uses many precisely focused radiation beams to treat tumors.

Durvalumab (Imfinzi) was approved by the Food and Drug Administration on February 16, 2018.

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